Diaphanous-related formin mDia2 regulates beta2 integrins to control hematopoietic stem and progenitor cell engraftment

Yang Mei; Xu Han; Yijie Liu; Jing Yang; Ronen Sumagin; Peng Ji

doi:10.1038/s41467-020-16911-4

Diaphanous-related formin mDia2 regulates beta2 integrins to control hematopoietic stem and progenitor cell engraftment

Yang Mei^*, Xu Han, Yijie Liu, Jing Yang, Ronen Sumagin, Peng Ji^*

^*Corresponding author for this work

Pathology

Research output: Contribution to journal › Article › peer-review

14 Scopus citations

Abstract

Bone marrow engraftment of the hematopoietic stem and progenitor cells (HSPCs) involves homing to the vasculatures and lodgment to their niches. How HSPCs transmigrate from the vasculature to the niches is unclear. Here, we show that loss of diaphanous-related formin mDia2 leads to impaired engraftment of long-term hematopoietic stem cells and loss of competitive HSPC repopulation. These defects are likely due to the compromised trans-endothelial migration of HSPCs since their homing to the bone marrow vasculatures remained intact. Mechanistically, loss of mDia2 disrupts HSPC polarization and induced cytoplasmic accumulation of MAL, which deregulates the activity of serum response factor (SRF). We further reveal that beta2 integrins are transcriptional targets of SRF. Knockout of beta2 integrins in HSPCs phenocopies mDia2 deficient mice. Overexpression of SRF or beta2 integrins rescues HSPC engraftment defects associated with mDia2 deficiency. Our findings show that mDia2-SRF-beta2 integrin signaling is critical for HSPC lodgment to the niches.

Original language	English (US)
Article number	3172
Journal	Nature communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-16911-4
State	Published - Dec 1 2020

Funding

We thank Baobing Zhao (Shangdong University, China) for technical assistance, Matthew DeBerge, Edward Thorp, and William A. Muller for sharing the fluorescence microscope and other resources, and Naren Ramanan for providing the SRF-VP16 construct. We are grateful to the Northwestern University Center for Advanced Microscopy core for the help with the imaging experiments and Zheng Jenny Zhang for the help with intrafemoral injection. This work was supported by National Institute of Diabetes and Digestive and Kidney Disease (NIDDK) grant R01-DK102718 (P.J.), R01-DK124220 (P.J.), National Heart, Lung, and Blood Institute grant R01-HL148012 (P.J.) and Department of Defense grant CA140119 and CA180214 (P.J.). X.H. is a recipient of an American Heart Association postdoctoral research award. P.J. is a recipient of a Leukemia and Lymphoma Society Scholar Award and a Harrington Discovery Institute Scholar Award.

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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title = "Diaphanous-related formin mDia2 regulates beta2 integrins to control hematopoietic stem and progenitor cell engraftment",

abstract = "Bone marrow engraftment of the hematopoietic stem and progenitor cells (HSPCs) involves homing to the vasculatures and lodgment to their niches. How HSPCs transmigrate from the vasculature to the niches is unclear. Here, we show that loss of diaphanous-related formin mDia2 leads to impaired engraftment of long-term hematopoietic stem cells and loss of competitive HSPC repopulation. These defects are likely due to the compromised trans-endothelial migration of HSPCs since their homing to the bone marrow vasculatures remained intact. Mechanistically, loss of mDia2 disrupts HSPC polarization and induced cytoplasmic accumulation of MAL, which deregulates the activity of serum response factor (SRF). We further reveal that beta2 integrins are transcriptional targets of SRF. Knockout of beta2 integrins in HSPCs phenocopies mDia2 deficient mice. Overexpression of SRF or beta2 integrins rescues HSPC engraftment defects associated with mDia2 deficiency. Our findings show that mDia2-SRF-beta2 integrin signaling is critical for HSPC lodgment to the niches.",

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AU - Sumagin, Ronen

AU - Ji, Peng

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Diaphanous-related formin mDia2 regulates beta2 integrins to control hematopoietic stem and progenitor cell engraftment

Abstract

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